Synthesis
Part B: Synthesis of 2,4,6-trichloro-5-fluoropyrimidine. Under stirring conditions (note the exothermic reaction), finely powdered 5-fluoro-6-hydroxy-2,4(1H,3H)-pyrimidinedione (74 g, 0.507 mol) was added to phosphorus oxychloride (POCl3, 232 mL, 2.5 mol) in a batch over a period of 30 min. After the addition was completed, the reaction mixture was maintained at 60 °C and N,N-dimethylaniline (65 mL) was slowly added dropwise via syringe. Upon completion of the dropwise addition, the reaction system was heated to 100-110 °C (internal temperature) and the reaction was continued until the reaction was determined to be complete by TLC or other appropriate method, which typically took 4-8 hours. Upon completion of the reaction, the mixture is cooled to room temperature, followed by careful removal of most of the remaining phosphorous trichloride by vacuum distillation at 80-90°C (note: some of the product may be distilled out with POCl3). The residue was slowly poured into ice water (~1 L) and stirred for 30 min. Extraction was carried out with ether (1 x 400 mL, 2 x 150 mL), the organic phases were combined and washed sequentially with water and saturated saline, and dried over anhydrous magnesium sulfate. The desiccant was removed by filtration, and the ether was removed by atmospheric pressure distillation to obtain the crude product. The crude product was purified by distillation under reduced pressure to afford the target product 2,4,6-trichloro-5-fluoropyrimidine (28.8 g, 28% yield) as a low melting point white crystalline solid (boiling point 80-85 °C, 12 mmHg).LCMS analysis: (M + H)+: not detected.
References
[1] Patent: WO2009/61879, 2009, A1. Location in patent: Page/Page column 64
[2] Patent: WO2013/82388, 2013, A1. Location in patent: Page/Page column 36; 70
